tbuckley/cabot-search huggingface dataset:
The Lung Allograft Microbiome Associates with Pepsin, Inflammation, and Primary Graft Dysfunction
Authors: John E. McGinniss, Samantha A. Whiteside, Rebecca A. Deek, Aurea Simon-Soro, Jevon Graham-Wooten, Michelle Oyster, Melanie D. Brown, Edward Cantu, Joshua M. Diamond, Hongzhe Li, Jason D. Christie, Frederic D. Bushman, Ronald G. Collman
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Primary graft dysfunction (PGD) is the principal cause of early morbidity and mortality after lung transplantation. The lung microbiome has been implicated in later transplantation outcomes but has not been investigated in PGD. Objectives: To define the peritransplant bacterial lung microbiome and relationship to host response and PGD. Methods: This was a single-center prospective cohort study. Airway lavage samples from donor lungs before organ procurement and recipient allografts immediately after implantation underwent bacterial 16S ribosomal ribonucleic acid gene sequencing. Recipient allograft samples were analyzed for cytokines by multiplex array and pepsin by ELISA. Measurements and Main Results: We enrolled 139 transplant subjects and obtained donor lung (n = 109) and recipient allograft (n = 136) samples. Severe PGD (persistent grade 3) developed in 15 subjects over the first 72 hours, and 40 remained without PGD (persistent grade 0). The microbiome of donor lungs differed from healthy lungs, and recipient allograft microbiomes differed from donor lungs. Development of severe PGD was associated with enrichment in the immediate postimplantation lung of oropharyngeal anaerobic taxa, particularly Prevotella. Elevated pepsin, a gastric biomarker, and a hyperinflammatory cytokine profile were present in recipient allografts in severe PGD and strongly correlated with microbiome composition. Together, immediate postimplantation allograft Prevotella/Streptococcus ratio, pepsin, and indicator cytokines were associated with development of severe PGD during the 72-hour post-transplantation period (area under the curve = 0.81). Conclusions: Lung allografts that develop PGD have a microbiome enriched in anaerobic oropharyngeal taxa, elevated gastric pepsin, and hyperinflammatory phenotype. These findings suggest a possible role for peritransplant aspiration in PGD, a potentially actionable mechanism that warrants further investigation.
Poly(ADP-ribose) promotes toxicity of <i>C9ORF72</i> arginine-rich dipeptide repeat proteins
Authors: Junli Gao, Quinlan T. Mewborne, Amandeep Girdhar, Udit Sheth, Alyssa N. Coyne, Ritika Punathil, Bong Gu Kang, Morgan Dasovich, Austin Veire, Mariely DeJesus Hernandez, Shuaichen Liu, Zheng Shi, Ruxandra Dafinca, Elise Fouquerel, Kevin Talbot, Tae-In Kam, Yong-Jie Zhang, Dennis Dickson, Leonard Petrucelli, Marka van Blitterswijk, Lin Guo, Ted M. Dawson, Valina L. Dawson, Anthony K. L. Leung, Thomas E. Lloyd, Tania F. Gendron, Jeffrey D. Rothstein, Ke Zhang
Journal: Science Translational Medicine (2022)

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72 , play a critical role in C9ORF72 -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.
A shift in lung macrophage composition is associated with COVID-19 severity and recovery
Authors: Steven T. Chen, Matthew D. Park, Diane Marie Del Valle, Mark Buckup, Alexandra Tabachnikova, Ryan C. Thompson, Nicole W. Simons, Konstantinos Mouskas, Brian Lee, Daniel Geanon, Darwin D’Souza, Travis Dawson, Robert Marvin, Kai Nie, Zhen Zhao, Jessica LeBerichel, Christie Chang, Hajra Jamal, Guray Akturk, Udit Chaddha, Kusum Mathews, Samuel Acquah, Stacey-Ann Brown, Michelle Reiss, Timothy Harkin, Marc Feldmann, Charles A. Powell, Jaime L. Hook, Seunghee Kim-Schulze, Adeeb H. Rahman, Brian D. Brown, Noam D. Beckmann, Sacha Gnjatic, Ephraim Kenigsberg, Alexander W. Charney, Miriam Merad
Journal: Science Translational Medicine (2022)

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue–resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.
Cold shock domain–containing protein E1 is a posttranscriptional regulator of the LDL receptor
Authors: Geoffrey A. Smith, Arun Padmanabhan, Bryan H. Lau, Akhil Pampana, Li Li, Clara Y. Lee, Angelo Pelonero, Tomohiro Nishino, Nandhini Sadagopan, Vivian Q. Xia, Rajan Jain, Pradeep Natarajan, Roland S. Wu, Brian L. Black, Deepak Srivastava, Kevan M. Shokat, John S. Chorba
Journal: Science Translational Medicine (2022)

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain–containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3′ untranslated region and regulated atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens in a tissue culture model, we identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies. Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, we showed that hepatic gene silencing of Csde1 treated diet-induced dyslipidemia in mice to a similar degree as Pcsk9 silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. Our approach of modeling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, may serve as a generalizable template for the identification of therapeutic targets in other human disease states.
Injectable Prevascularized Mature Adipose Tissues (iPAT) to Achieve Long‐Term Survival in Soft Tissue Regeneration
Authors: Fiona Louis, Yoshihiro Sowa, Shinji Irie, Yuriko Higuchi, Shiro Kitano, Osam Mazda, Michiya Matsusaki
Journal: Advanced Healthcare Materials (2022)

Soft tissue regeneration remains a challenge in reconstructive surgery. So far, both autologous fat implantations and artificial implants methods used in clinical applications lead to various disadvantages and limited lifespan. To overcome these limitations and improve the graft volume maintenance, reproducing a mature adipose tissue already including vasculature structure before implantation can be the solution. Therefore, injectable prevascularized adipose tissues (iPAT) are made from physiological collagen microfibers mixed with human mature adipocytes, adipose-derived stem cells, and human umbilical vein endothelial cells, embedded in fibrin gel. Following murine subcutaneous implantation, the iPAT show a higher cell survival (84% ± 6% viability) and volume maintenance after 3 months (up to twice heavier) when compared to non-prevascularized balls and liposuctioned fat implanted controls. This higher survival can be explained by the greater amount of blood vessels found (up to 1.6-fold increase), with balanced host anastomosis (51% ± 1% of human/mouse lumens), also involving infiltration by the lymphatic and neural vasculature networks. Furthermore, with the cryopreservation possibility enabling their later reinjection, the iPAT technology has the merit to allow noninvasive soft tissue regeneration for long-term outcomes.
Lessons from a large-scale COVID-19 vaccine trial
Authors: Ranjeet Singh Mahla, Lynn B. Dustin
Journal: Journal of Clinical Investigation (2022)

Global vaccination coverage remains indispensable in combatting the ongoing SARS-CoV-2 pandemic. Safety, efficacy, and durability of immune protection are the key parameters of randomized controlled trials (RCTs) and are essential for vaccine approvals, global distribution, and comprehensive population-vaccination programs. Immune protection from either vaccination or natural infection decreases over time, further challenged by rapid viral evolution. In this issue of the JCI, Sobieszczyk and colleagues report an update on the safety, efficacy, and durability of immune protection of AZD12222 in a large-scale, multinational, Phase III RCT. They report that protection lasted through 6 months, with immunity waning after 180 days. The study also highlights challenges facing vaccine trials, including the need for early unblinding for vulnerable participants, which may affect outcome measurements. Another challenge is to ensure fair representation of marginalized and minority ethnic groups in vaccine safety and efficacy studies worldwide.
Fast Construction of Biomimetic Organic–Inorganic Interface by Crosslinking of Calcium Phosphate Oligomers: A Strategy for Instant Regeneration of Hard Tissue
Authors: Lumiao Yan, Chen Zheng, Ding Yuan, Zhengxi Guo, Yihao Cui, Zhijian Xie, Zhi Chen, Ruikang Tang, Zhaoming Liu
Journal: Advanced Healthcare Materials (2022)

The organic-inorganic structure in biological hard tissues ensures their marvelous characteristics but these hybrids are easily destroyed by the demineralization of inorganic components, e.g., the damage of dentin. Current clinical materials for hard tissue regeneration commonly act as "fillers" and their therapeutic effect is limited by the failures of biological-linked organic-inorganic interface reconstruction. Herein, a fast in situ crosslinking of calcium phosphate oligomers (CPOs) on collagen matrixes for efficient organic-inorganic interface re-construction, which can result in a biomimetic hybrid, is demonstrated. By using damaged dentin as an example, the inorganic ionic crosslinking can instantly infiltrate into the dentin matrix to rebuild a dense and continuous calcium phosphate-collagen hybrid within only 5 min, where the structurally integrated organic-inorganic interface is identical to natural dentin. As a result, the damaged dentin can be fully recovered to a healthy one, which is superior to any current dentin treatments. The fast construction of biomimetic hybrid by inorganic ionic crosslinking provides a promising strategy for hard tissue repair and follows great potentials of CPOs as advanced biomedical materials in future.
Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death
Authors: Nolan T. Carew, Heidi M. Schmidt, Shuai Yuan, Joseph C. Galley, Robert Hall, Helene M. Altmann, Scott A. Hahn, Megan P. Miller, Katherine C. Wood, Bethann Gabris, Margaret C. Stapleton, Sean Hartwick, Marco Fazzari, Yijen L. Wu, Mohamed Trebak, Brett A. Kaufman, Charles F. McTiernan, Francisco J. Schopfer, Placido Navas, Patrick H. Thibodeau, Dennis M. McNamara, Guy Salama, Adam C. Straub
Journal: Journal of Clinical Investigation (2022)

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.
Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade
Authors: Arnab Ghosh, Judith Michels, Riccardo Mezzadra, Divya Venkatesh, Lauren Dong, Ricardo Gomez, Fadi Samaan, Yu-Jui Ho, Luis Felipe Campesato, Levi Mangarin, John Fak, Nathan Suek, Aliya Holland, Cailian Liu, Mohsen Abu-Akeel, Yonina Bykov, Hong Zhong, Kelly Fitzgerald, Sadna Budhu, Andrew Chow, Roberta Zappasodi, Katherine S. Panageas, Olivier de Henau, Marcus Ruscetti, Scott W. Lowe, Taha Merghoub, Jedd D. Wolchok
Journal: Journal of Clinical Investigation (2022)

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.
Functional cure of hepatitis B requires silencing covalently closed circular and integrated hepatitis B virus DNA
Authors: Marc G. Ghany, Anna S. Lok
Journal: Journal of Clinical Investigation (2022)

Chronic hepatitis B virus (HBV) infection remains a major global health problem. Hepatitis B surface antigen (HBsAg) loss has been accepted as the definition of a functional HBV cure. Recent studies found that while covalently closed circular DNA (cccDNA) is the predominant source of HBsAg in hepatitis B e antigen-positive (HBeAg-positive) patients, integrated HBV DNA (iDNA) is the main source in HBeAg-negative patients. Consequently, achieving a functional HBV cure will require not only silencing of cccDNA but also iDNA. Assays that distinguish the source of HBsAg are needed to evaluate emerging therapies. In this issue of the JCI, Grudda et al. developed a PCR-based assay that differentiated the source of HBsAg and explored the contributing sources of HBsAg in patients on nucleos(t)ide analog antivirals. These findings provide a tool for understanding the contribution of iDNA in HBV infection and may guide therapies toward a functional HBV cure.
Emerging roles of extracellular vesicles in normal and malignant hematopoiesis
Authors: Guohuan Sun, Quan Gu, Junke Zheng, Hui Cheng, Tao Cheng
Journal: Journal of Clinical Investigation (2022)

Hematopoietic stem cells, regulated by their microenvironment (or "niche"), sustain the production of mature blood and immune cells. Leukemia cells remodel the microenvironment to enhance their survival, which is accompanied by the loss of support for normal hematopoiesis in hematologic malignancies. Extracellular vesicles (EVs) mediate intercellular communication in physiological and pathological conditions, and deciphering their functions in cell-cell interactions in the ecosystem can highlight potential therapeutic targets. In this Review, we illustrate the utility of EVs derived from various cell types, focusing on the biological molecules they contain and the behavioral alterations they can induce in recipient cells. We also discuss the potential for clinical application in hematologic malignancies, including EV-based therapeutic regimens, drug delivery via EVs, and the use of EVs (or their cargoes) as biomarkers.
Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months
Authors: Magdalena E. Sobieszczyk, Jill Maaske, Ann R. Falsey, Stephanie Sproule, Merlin L. Robb, Robert W. Frenck, Hong-Van Tieu, Kenneth H. Mayer, Lawrence Corey, Kathleen M. Neuzil, Tina Tong, Margaret Brewinski Isaacs, Holly Janes, Himanshu Bansal, Lindsay M. Edwards, Justin A. Green, Elizabeth J. Kelly, Kathryn Shoemaker, Therese Takas, Tom White, Prakash Bhuyan, Tonya Villafana, and Ian Hirsch
Journal: Journal of Clinical Investigation (2022)

BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.
Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer
Authors: R. Bryan Bell, Michael Gough, Marka Crittenden, Kristina Young
Journal: Journal of Clinical Investigation (2022)

Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor β (TGF-β) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI, Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-β. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-β may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.
The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity
Authors: Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong
Journal: Journal of Clinical Investigation (2022)

Forkhead box O transcriptional factors, especially FoxO1 and FoxO3a, play critical roles in physiologic and pathologic immune responses. However, the function of FoxO4, another main member of the FoxO family, in lymphoid cells is still poorly understood. Here, we showed that loss of FoxO4 in T cells augmented IFN-γ production of Th1 cells in vitro. Correspondingly, conditional deletion of FoxO4 in CD4+ T cells enhanced T cell-specific responses to Listeria monocytogenes infection in vivo. Genome-wide occupancy and transcriptomic analyses identified Dkk3 (encoding the Dickkopf-3 protein) as a direct transcriptional target of FoxO4. Consistent with the FoxO4-DKK3 relationship, recombinant DKK3 protein restored normal levels of IFN-γ production in FoxO4-deficient Th1 cells through the downregulation of lymphoid enhancer-binding factor 1 (Lef1) expression. Together, our data suggest a potential FoxO4/DKK3 axis in Th1 cell differentiation, providing what we believe to be an important insight and supplement for FoxO family proteins in T lymphocyte biology and revealing a promising target for the treatment of immune-related diseases.